Bloch-Sulzberger Syndrome: Etiological, Pathogenetic and Clinical Features of Central Nervous System Diseases


  • L.V. Shalkevych State Educational Institution «Belarusian Medical Academy of Postgraduate Education», Minsk
  • A.I. Kudlach State Educational Institution «Belarusian Medical Academy of Postgraduate Education», Minsk



Bloch-Sulzberger syndrome, incontinentia pigmenti, neurological disorders, children


This article describes the issues of the etiology, pathogenesis, clinical manifestations, diagnosis, treatment and prevention of neurological complications in Bloch-Sulzberger syndrome as an optional (small) manifestation of this disease, with the focus on the features of IKBKG gene mutation in cells and tissues of the nervous system. The article is illustrated with a case report of our own observation of family inheritance of this disease in two girls (native sisters). It is of particular interest because of differences in pathogenetic mechanisms of genetic defect in the cells and tissues of the central nervous system in Bloch-Sulzberger syndrome among different patients, even in case of their consanguinity.


Aradhya S, Woffendin H, Jakins T, Bardaro T, Esposito T, Smahi A, Shaw C, Levy M, Munnich A, D'Urso M, Lewis RA, Kenwrick S, Nelson DL. A recurrent deletion in the ubiquitously expressed NEMO (IKK-γ) gene accounts for the vast majority of incontinentia pigmenti mutations. Hum Mol Genet 2001;10:2171–2179. doi:10.1093/hmg/10.19.2171.

Bachevalier F, Marchal C, Di Cesare MP, Antunes A, Truchetet F. Atteinte neurologique létale au cours d'une incontinentia pigmenti. Ann Dermatol Venereol 2003;130:1139–1142. doi:AD-12-2003-130-12-0151-9638-101019- ART8.

Berlin AL, Paller AS, Chan LS. Incontinentia pigmenti: a review and update on the molecular basis of pathophysiology. J Am Acad Dermatol 2002;47:169–187. doi:10.1067/mjd.2002.125949

Brown KD, Claudio E, Siebenlist U. The roles of the classical and alternative nuclear factor-kappaB pathways: potential implications for autoimmunity and rheumatoid arthritis. Arthritis Res Ther 2008;10:212. doi: 10.1186/ar2457

Chelly J, Khelfaoui M, Francis F, Chérif B, Bienvenu T. Genetics and pathophysiology of mental retardation. Eur J Hum Genet 2006;14:701–713. doi:10.1038/ sj.ejhg.5201595.

Cheng LE, Kanwar B, Tcheurekdjian H, et al. Persistent systemic inflammation and atypical enterocolitis in patients with NEMO syndrome. Clin Immunol 2009;132:124-131. doi: 10.1016/j.clim.2009.03.514.

Chiurazzi P, Schwartz CE, Gecz J, Neri G. XLMR genes: update 2007. Eur J Hum Genet 2008;16:422–434. doi:10.1038/sj.ejhg.5201994.

Fiorillo L, Sinclair DB, O'Byrne ML, Krol AL. Bilateral cerebrovascular accidents in incontinentia pigmenti. Pediatr Neurol 2003;29:66–68. doi:10.1016/S0887-8994(03)00144-9.

Fusco F, Bardaro T, Fimiani G, Mercadante V, Miano MG, Falco G, Israël A, Courtois G, D'Urso M, Ursini MV. Molecular analysis of the genetic defect in a large cohort of IP patients and identification of novel NEMO mutations interfering with NF-κB activation. Hum Mol Genet 2004;13:1763–1773. doi:10.1093/hmg/ddh192.

Fusco F, Pescatore A, Bal E, Ghoul A, Paciolla M, Lioi MB, D'Urso M, Rabia SH, Bodemer C, Bonnefont JP, Munnich A, Miano MG, Smahi A, Ursini MV. Alterations of the IKBKG locus and diseases: an update and a report of 13 novel mutations. Hum Mutat 2008;29:595–604. doi:10.1002/ humu.20739.

Fusco F, Paciolla M, Napolitano F, Pescatore A, D'Addario I, Bal E, Lioi MB, Smahi A, Miano MG, Ursini MV. Genomic architecture at the Incontinentia Pigmenti locus favours de novo pathological alleles through different mechanisms. Hum Mol Genet 2012;21:1260–1271. doi:10.1093/hmg/ddr556.

Galluzzi L, Vitale I, Abrams JM, Alnemri ES, Baehrecke EH, Blagosklonny MV, Dawson TM, Dawson VL, El-Deiry WS, Fulda S, Gottlieb E, Green DR, Hengartner MO, Kepp O, Knight RA, Kumar S, Lipton SA, Lu X, Madeo F, Malorni W, Mehlen P, Nuñez G, Peter ME, Piacentini M, Rubinsztein DC, Shi Y, Simon HU, Vandenabeele P, White E, Yuan J, et al. Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012. Cell Death Differ 2012;19:107–120. doi:10.1038/cdd.2011.96

Garcia-Zepeda EA, Rothenberg ME, Ownbey RT, Celstin J, Leder P, Luster AD. Human eotaxin is a specific chemoattractant for eosinophil cells and provides a new mechanism to explain tissue eosinophilia. Nat Med 1996;2:449–456. doi:10.1038/nm0496-449.

Goldberg MF. The skin is not the predominant problem in incontinentia pigmenti. Arch Dermatol 2004;140:748–750. doi:10.1001/archderm.140.6.748.

Hennel SJ, Ekert PG, Volpe JJ, Inder TE. Insights into the pathogenesis of cerebral lesions in incontinentia pigmenti. Pediatr Neurol 2003;29:148– 150. doi:10.1016/S0887-8994(03)00150-4.

Jean-Baptiste S, O’Toole EA, Chen M, Guitart J, Paller A, Chan LS. Expression of eotaxin, an eosinophil-selective chemokine, parallels eosinophil accumulation in the vesiculobullous stage of incontinentia pigmenti. Clin Exp Immunol 2002;127:470–478. doi:10.1046/j.1365-2249.2002.01755.x.

Kroemer G, Galluzzi L, Vandenabeele P, Abrams J, Alnemri ES, Baehrecke EH, Blagosklonny MV, El-Deiry WS, Golstein P, Green DR, Hengartner M, Knight RA, Kumar S, Lipton SA, Malorni W, Nuñez G, Peter ME, Tschopp J, Yuan J, Piacentini M, Zhivotovsky B, Melino G. Classification of cell death: recommendations of the Nomenclature Committee on Cell Death 2009. Cell Death Differ 2009;16:3–11. doi:10.1038/cdd.2008.150.

Landy SJ, Donnai D. Incontinentia pigmenti (Bloch-Sulzberger syndrome). J Med Genet 1993;30:53–59. doi:10.1136/jmg.30.1.53.

Meuwissen MEC, Mancini GMS. Neurological findings in incontinentia pigmenti; a review. Eur J Med Genet 2012;55:323–331. doi:10.1016/j. ejmg.2012.04.007.

Minić S, Trpinac D, Obradović M. Systematic review of central nervous system anomalies in incontinentia pigmenti. Orphanet Journal of Rare Diseases 2013;8:1-10. doi: 10.1186/1750-1172-8-25

Morgan J.D. Incontinentia pigmenti (Bloch-Sulzberger syndrome): A report of four additinal cases. Am J Dis Child 1971;128: 546-547.

Pascual-Castroviejo I, Pascual-Pascual SI, Velázquez-Fragua R, Martinez V:Incontinentia pigmenti. Clinical and neuroimaging findings in a series of 12 patients. Neurologia 2006;21:239–248.

Prevalence of rare diseases: Bibliographic data. Orphanet Report Series: 2012;1. [].

Rosman N.P. Incontinentia pigmenti. In: Susuki F., Kamoshita S., Casaer P. (eds.). Fetal and Perinatal Neurology. Basel, Karger 1992;l74-186.

Sanz AB, Sanchez-Niño MD, Ramos AM, et al. NF-kappaB in renal inflammation. J Am Soc Nephrol 2010;21:1254‐1262. doi: 10.1681/ASN.2010020218

Scheuerle A, Ursini MV. Incontinentia pigmenti (Bloch-Sulzberger syndrome). University of Washington, Seattle (WA): GeneReviews:2008;22.

Sefiani A, Abel L, Heuertz S. et al. The gene for incontinentia pigmenti is assigned to Xq28. Genomics 1989;4:427-429.

Smahi A, Courtois G, Vabres P, Yamaoka S, Heuertz S, Munnich A, Israël A, Heiss NS, Klauck SM, Kioschis P, Wiemann S, Poustka A, Esposito T, Bardaro T, Gianfrancesco F, Ciccodicola A, D'Urso M, Woffendin H, Jakins T, Donnai D, Stewart H, Kenwrick SJ, Aradhya S, Yamagata T, Levy M, Lewis RA, Nelson DL. Genomic rearrangement in NEMO impairs NF-κB activation and is a cause of incontinentia pigmenti. The International Incontinentia Pigmenti (IP) Consortium. Nature 2000;405:466–472. doi:10.1038/35013114

Takada H, Nomura A, Ishimura M, Ichiyama M, Ohga S and Hara T. NEMO mutation as a cause of familial occurrence of Behçet's disease in female patients. Clin Genet 2010;78:575-579. doi: 10.1111/j.1399-0004.2010.01432.x.

Voy`nova VM, Novy`kov PV, Kazanceva LZ. Sy`ndrom Bloxa-Sul`czbergera u detej. Rossy`jsky`j vestny`k pery`natology`y` y` pedy`atry`y` 1999;5;25-28.

Kalamkaryan AA, Mordovcev VN, Trofy`mova LV. Kly`ny`cheskaya dermatology`ya: Redky`e y` aty`py`chnыe dermatozы. Erevan: Ajastan. 1989;336.

Kly`ny`cheskaya dermatovenerology`ya. Rukovodstvo dlya vrachej. Pod red. Yu.K. Skry`pky`na, Yu.N. Butova. T 2. M.: GЭOTAR-Medy`a. 2009;462.

Shal`kevy`ch LV, L`vova OA. K voprosu o novыx defy`ny`cy`yax эpy`lepsy`y`. Astraxansky`j medy`cy`nsky`j zhurnal 2014;2;29-34.





Original Researches